CN104262263A - N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof - Google Patents
N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104262263A CN104262263A CN201410438745.6A CN201410438745A CN104262263A CN 104262263 A CN104262263 A CN 104262263A CN 201410438745 A CN201410438745 A CN 201410438745A CN 104262263 A CN104262263 A CN 104262263A
- Authority
- CN
- China
- Prior art keywords
- amine
- reaction
- bcr
- piperazine
- diphenylpyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- TZGVTJQEPWNPGD-UHFFFAOYSA-N n,6-diphenylpyrimidin-4-amine Chemical compound C=1C(C=2C=CC=CC=2)=NC=NC=1NC1=CC=CC=C1 TZGVTJQEPWNPGD-UHFFFAOYSA-N 0.000 title claims abstract description 18
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 title abstract description 23
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 118
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 59
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 59
- 238000000967 suction filtration Methods 0.000 claims description 57
- 229940118364 Bcr-Abl inhibitor Drugs 0.000 claims description 53
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- 239000000243 solution Substances 0.000 claims description 35
- -1 6-chloro-N-substituted-phenyl pyrimidine-4-amine Chemical class 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 34
- RUYGUQHWXZCLST-UHFFFAOYSA-N 2,5-diphenylpyrimidin-4-amine Chemical compound NC1=NC(C=2C=CC=CC=2)=NC=C1C1=CC=CC=C1 RUYGUQHWXZCLST-UHFFFAOYSA-N 0.000 claims description 30
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical class ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims description 15
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 claims description 15
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
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- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 0 C*(C=C1)C=C1Nc1ncnc(-c(cc2)ccc2C(N(CC2)CCN2C(c2ccccc2)=O)=O)c1 Chemical compound C*(C=C1)C=C1Nc1ncnc(-c(cc2)ccc2C(N(CC2)CCN2C(c2ccccc2)=O)=O)c1 0.000 description 1
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- 238000000021 kinase assay Methods 0.000 description 1
- BVUQKCCKUOSAEV-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=[C-]C=C1 BVUQKCCKUOSAEV-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as a preparation method and application thereof. A structural formula of the inhibitors is shown in the specification, wherein in the structural formula, R is a mono-substituent or a di-substituent, and the substituent is alkyl or halogen; R1 is a mono-substituent or a di-substituent, and the substituent is alkyl or halogen. The series of inhibitors have a certain inhibiting effect on ABL1 kinase in vitro, can inhibit tumor cell proliferation and can be used for preparing antitumor drugs, especially CML (chronic myelocytic leukemia) drugs. The preparation method of the N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors, which is provided by the invention, has the advantages of easiness in obtainment of raw materials, mild reaction conditions, simplicity in operation of reaction processes and cheap used reagents.
Description
Technical field
The invention belongs to biomedicine technical field, relate to a kind of anticancer compound, particularly a kind of N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor and its preparation method and application.
Background technology
Chronic myelocytic leukemia is the malignant tumour betiding blood system, sickness rate is higher, account for 15% ~ 20% of adult leukemia, all can fall ill at each age group, be common with person in middle and old age's case, be one of principal disease threatening human life, its molecular mechanism is Bcr-Abl kinases constitutive activation.For leukemic treatment, turn to molecular targeted therapy from traditional chemotherapeutics, interferon therapy, overcome chemotherapeutics targeting low, the shortcoming that toxic side effect is large.The exploitation of small molecules targeted inhibition agent makes the treatment of chronic myelocytic leukemia achieve revolutionary progress, but, along with clinical application finds, easily there are resistance mutation, other signal path compensatory activation etc. and all affect the result for the treatment of that medicine cannot reach expection in Bcr-Abl kinases.The research and development of the therefore new anti-leukemia medicine for resistance mutation are one of the focus and difficulties of current pharmaceutical field.
Summary of the invention
The object of the present invention is to provide a kind of N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor and its preparation method and application, can be applied to the preparation of cancer therapy drug.
For achieving the above object, the present invention is achieved through the following technical solutions:
A kind of N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, have following structural formula:
Wherein, R is monosubstituted base or disubstituted, and substituting group is alkyl or halogen; R
1for monosubstituted base or disubstituted, substituting group is alkyl or halogen.
When described R is monosubstituted base, substituting group is positioned at the ortho position of amido on phenyl ring, a position or contraposition; R
1during for monosubstituted base, substituting group is positioned at the ortho position of carboxyl on phenyl ring, a position or contraposition;
Described R, R
1for time disubstituted, substituting group is identical or different, and the position of substitution is adjacent or alternate.
A kind of N, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, comprises following operation:
1) 4,6-dichloro pyrimidines prepare 6-chloro-N-substituted-phenyl pyrimidine-4-amine with containing substituent aniline generation nucleophilic substitution reaction;
2) 6-chloro-N-substituted-phenyl pyrimidine-4-amine with through Suzuki linked reaction prepared by 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid to Carboxybenzeneboronic acid;
3) react containing substituent phenylformic acid and piperazine the piperazine preparing monoamide;
4) piperazine of 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid and monoamide is by condensation reaction, obtains N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
Described step 1) concrete operations be: by 4,6-dichloro pyrimidine be dissolved in Virahol containing substituent aniline, the vitriol oil is dripped under the condition stirred, heating reflux reaction, be cooled to room temperature after having reacted, be placed on 4 DEG C of refrigerator overnight, then suction filtrations, dry cake, obtains 6-chloro-N-substituted-phenyl pyrimidine-4-amine crude product;
Described step 2) concrete operations be: by chloro-for 6-N-substituted-phenyl pyrimidine-4-amine crude product be dissolved in the mixed solvent of acetonitrile and water to Carboxybenzeneboronic acid; add cesium carbonate, tetrakis triphenylphosphine palladium; with nitrogen protection; isothermal reaction 24 ~ 48 hours at 90 DEG C; react after heat suction filtration; by filtrate evaporate to dryness removing acetonitrile; be extracted with ethyl acetate again, to be adjusted to pH be slightly acidic to aqueous phase concentrated hydrochloric acid; separate out solid; then suction filtration, dry cake, obtains 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid.
Described step 3) concrete operations be: under condition of ice bath, added by piperazine in concentrated hydrochloric acid, then at room temperature stirring reaction spends the night, then suction filtration, and dry cake obtains piperazine dihydrochloride; To dissolve containing substituent phenylformic acid anhydrous tetrahydro furan, add CDI, room temperature reaction 2 hours, then dropwise joins in the saturated nacl aqueous solution of piperazine dihydrochloride and piperazine by it, room temperature reaction 6 hours, react rear evaporate to dryness tetrahydrofuran (THF), be extracted with ethyl acetate, aqueous phase sodium hydroxide solution is adjusted to pH=10, then is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, the then suction filtration of extraction, evaporate to dryness ethyl acetate, obtain the piperazine of monoamide.
Described step 4) concrete operations be: under condition of ice bath, isobutyl chlorocarbonate is added drop-wise in the tetrahydrofuran (THF) containing triethylamine, be stirred to and produce thick white shape colloid, then the tetrahydrofuran solution of 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid and triethylamine is dripped wherein, dropwise the bath of recession deicing, at room temperature reaction is spent the night, generate activity anhydride, then the piperazine of monoamide is dripped wherein, at room temperature react 24 hours, reaction terminates rear evaporate to dryness tetrahydrofuran (THF), wash with saturated sodium bicarbonate successively, extraction into ethyl acetate, the organic phase anhydrous sodium sulfate drying of extraction, last suction filtration, evaporate to dryness ethyl acetate, obtain crude product, N is obtained again through pillar layer separation, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
The described preparation process to Carboxybenzeneboronic acid is: para-bromo toluene prepares grignard reagent p-tolylmagnesium bromide by grignard reaction, grignard reagent and trimethyl borate are obtained by reacting methylphenylboronic acid methyl esters, obtain methylphenylboronic acid to the hydrolysis of methylphenylboronic acid methyl esters, methylphenylboronic acid oxidation is obtained Carboxybenzeneboronic acid.
Preparation to the concrete operations of Carboxybenzeneboronic acid is: soaked by magnesium rod saturated ammonium chloride solution, the magnesium oxide on removing surface, be dried to anhydrous, then flask is put into, heating oxygen constantly in abstraction reaction system, question response system is cooled to room temperature, be rapidly in flask and add a little iodine grain, vacuumize, low-grade fever becomes brown color to magnesium rod surface, then rapid raised temperature, in system, the tetrahydrofuran solution initiation reaction of para-bromo toluene is slowly injected by syringe, back flow reaction was cooled to room temperature after 6 hours, under the low temperature agitation condition of-30 DEG C, the tetrahydrofuran solution reaction of slow injection trimethyl borate is spent the night.Then dilute hydrochloric acid hydrolysis, extraction into ethyl acetate, anhydrous sodium sulfate drying, suction filtration, evaporate to dryness removing ethyl acetate, recrystallization, hot suction filtration are carried out successively to reaction product, suction filtration after white solid separated out by the refrigerator that filtrate is placed in 4 DEG C, and drying obtains methylphenylboronic acid.To be dissolved in sodium hydroxide solution to methylphenylboronic acid, under condition of ice bath, slowly added the aqueous solution of potassium permanganate, Tetrabutyl amonium bromide by constant pressure funnel, after dropwising, at room temperature stirring reaction spends the night, by a small amount of ethanol cancellation reaction system, suction filtration, filtrate adjusts pH to acid with concentrated hydrochloric acid, separates out white solid, suction filtration, filtration cakes torrefaction is Carboxybenzeneboronic acid.
Described N, the application of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor in preparation Bcr-Abl inhibitor medicaments.
Described N, the application in antitumor drug prepared by 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
Described antitumor drug is the leukemic medicine for the treatment of.
Compared with prior art, the present invention has following beneficial effect:
The N with anti-tumor activity provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, be a kind of novel compound with anti-Bcr-Abl kinase activity, to Bcr-Abl kinases, there is good inhibit activities in vitro, can be used for the preparation of leukemia medicament.Bcr-Abl kinases plays a significant role at cell signalling with in transforming, and it impels the unlimited hyperplasia of the ripe granulocyte of CML by phosphorylation and a series of stream substrates of activation.Bcr-Abl does not express in normal cell, is the ideal targets for the treatment of CML.The object of Bcr-Abl inhibitor by suppressing Bcr-Abl kinase activity can reach treatment CML.Experimental result shows the N prepared by the present invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor can suppress the active of Bcr-Abl and the growth of inhibition tumor cell and propagation effectively, N prepared by explanation, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor can be used for preparation Bcr-Abl inhibitor medicaments and antitumor drug.
The N with anti-tumor activity provided by the invention, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, has raw material and is easy to get, and reaction conditions is gentle, and reaction process is simple to operate, the advantage that agents useful for same is cheap.
The N with anti-tumor activity provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, the Bcr-Abl kinase activity of its cell-proliferation activity and suppression and this disease-related can be suppressed K562 leukemia cell, can be applicable to the preparation of leukemia medicament.
Accompanying drawing explanation
Fig. 1 is N, the synthetic route chart of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor;
Wherein compound 1 is 4, 6-dichloro pyrimidine, compound 2 is the aniline replaced, compound 3 is 6-chloro-N-substituted-phenyl pyrimidine-4-amine, compound 4 is para-bromo toluene, compound 5 is p-tolylmagnesium bromide, compound 6 is to methylphenylboronic acid methyl esters, compound 7 is to methylphenylboronic acid, compound 8 is to Carboxybenzeneboronic acid, compound 9 is 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid, compound 10 is piperazine, compound 11 is piperazine dihydrochloride, compound 12 is piperazine one hydrochloride, compound 13 is for containing substituent phenylformic acid, compound 14 is active amide intermediate, compound 15 is the piperazine of monoamide, compound 16 is ultimate aim compound N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
What mark in figure is specially:
(a) .Mg, I
2, THF, backflow; (b) .B (OCH
3)
3,-30 DEG C; (c) .HCl, rt; (d) .KMnO
4, TBAB, NaOH/H
2o, rt; (e) .i-PrOH, conc.H
2sO
4, backflow; (f) .Pd (Pph
3)
4, Cs
2cO
3, MeCN/H
2o, 90 DEG C, N
2; (g) .CDI, THF, rt; (h) .conc.HCl; (i) .NaCl/H
2o; (j) .H
2o, rt; (k) .i-BuCOOCl, TEA, THF.
Embodiment
The invention provides a kind of N with anti-leukocythemia liveness, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, such Bcr-Abl inhibitor embodies good anti-leukocythemia liveness in vitro, can be applied to the preparation of leukemia medicament.
Be described in detail the present invention below in conjunction with drawings and Examples, the explanation of the invention is not limited.
N provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, its chemical structural formula is:
Wherein, R is monosubstituted base or disubstituted, and substituting group is alkyl or halogen; R
1for monosubstituted base or disubstituted, substituting group is alkyl or halogen.
When R is monosubstituted base, substituting group is positioned at the ortho position of amido on phenyl ring, a position or contraposition;
R
1during for monosubstituted base, substituting group is positioned at the ortho position of carboxyl on phenyl ring, a position or contraposition;
R, R
1for time disubstituted, substituting group is identical or different, and the position of substitution is adjacent or alternate.
N is described in detail, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor and method for screening active ingredients below in conjunction with the synthetic route shown in Fig. 1 and concrete synthesis example.
Embodiment 1
In the structural formula of this inhibitor, R
1for fluorine atom, be in ortho position, R is trifluoromethyl, is in contraposition, by following steps preparation (see Fig. 1):
1) 4,6-dichloro pyrimidines and p-trifluoromethylaniline generation nucleophilic substitution reaction prepare the chloro-N-of 6-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine;
4,6-dichloro pyrimidine 3.88g (26mmol) and p-trifluoromethylaniline 3.3g (20mmol) is dissolved in 40ml Virahol, under the condition stirred, dropwise adds the 1.5ml vitriol oil, heating reflux reaction 6 hours, monitoring reaction system.Be placed on 4 DEG C of refrigerator overnight after being cooled to room temperature, suction filtration after precipitation white solid, filter cake put dry in an oven, obtain the chloro-N-of 6-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine crude product 4.9g, productive rate 90%.
2) para-bromo toluene is prepared Carboxybenzeneboronic acid through grignard reaction, esterification, hydrolysis, oxidizing reaction;
Magnesium rod 3.6g (150mmol) is soaked 10 minutes with saturated ammonium chloride solution, wash magnesium oxide and the inorganic salt on 5 removing surfaces, anhydrous tetrahydro furan is placed in infrared Quick drying box after rinsing twice and dries, then two neck flasks are put into, heating oxygen constantly in abstraction reaction system, question response system is cooled to room temperature, be rapidly in two neck flasks and add 3 iodine grains, vacuumize, low-grade fever to magnesium rod surface is rapid raised temperature after becoming brown color, in system, the tetrahydrofuran solution 50ml initiation reaction of para-bromo toluene 17.1g (100mmol) is slowly injected by syringe, reaction system was cooled to room temperature after 6 hours by heating reflux reaction, be placed in-30 degrees Celsius of cryogenic thermostat stirring reaction baths, the tetrahydrofuran solution 50ml reaction of slow injection trimethyl borate 14.1g (150mmol) is spent the night.Add that 2mol/L hydrochloric acid 100ml is hydrolyzed 5 hours, extraction into ethyl acetate three times, merge organic phase anhydrous sodium sulfate drying, suction filtration, evaporate to dryness removing ethyl acetate, recrystallization (recrystallization solvent for use: water), hot suction filtration, filtrate is placed in that white solid suction filtration separated out by 4 DEG C of refrigerators, drying obtains methylphenylboronic acid 7.3g, productive rate 55%.To be dissolved in 1mol/L161mL sodium hydroxide solution to methylphenylboronic acid 7.3g (53.67mmol), under condition of ice bath, potassium permanganate 25.44g (161mmol), Tetrabutyl amonium bromide 0.54g (1.67mmol) aqueous solution 537ml is slowly added by constant pressure funnel, dropwise, remove ice bath, stirring at room temperature reaction is spent the night, by 20ml ethanol cancellation reaction system 1 hour, suction filtration, filtrate adjusts pH to 2 to separate out white solid with concentrated hydrochloric acid, suction filtration, filtration cakes torrefaction is Carboxybenzeneboronic acid crude product 7.0g, productive rate 80%;
3) the chloro-N-of 6-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine prepares 4-(6-{ [4-(trifluoromethyl) phenyl] amino } pyrimidine-4-yl) phenylformic acid with to Carboxybenzeneboronic acid through Suzuki linked reaction;
By chloro-for 6-N-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine 2.7g (10mmol), to Carboxybenzeneboronic acid (4-Carboxybenzeneboronic acid) 2g (12mmol), cesium carbonate 10g (30mmol), tetrakis triphenylphosphine palladium (four triphenyl phosphorus palladiums) 0.6g (0.5mmol) in 250ml round-bottomed flask; add acetonitrile, each 50ml of water; nitrogen protection, 90 DEG C of isothermal reactions 48 hours.Suction filtration while hot, filtrate evaporate to dryness acetonitrile, with ethyl acetate 20ml extraction twice, aqueous phase 6mol/L hydrochloric acid adjusts pH to 5, separate out white solid, suction filtration, filter cake is placed in baking oven inner drying, namely 4-(6-{ [4-(trifluoromethyl) phenyl] amino } pyrimidine-4-yl) phenylformic acid crude product 2.88g is obtained, productive rate 80%.
4) o-fluorobenzoic acid and piperazine prepare 1-(2-fluoro benzoyl) piperazine by condensation reaction;
100g concentrated hydrochloric acid (12mol/L) is placed in the round-bottomed flask of 250ml, under the condition of ice bath, slowly adds 40g Piperazine anhydrous, after adding, remove ice bath, room temperature reaction spends the night, suction filtration, filter cake is placed in baking oven inner drying, and gained white solid is piperazine dihydrochloride.Take the tetrahydrofuran (THF) that 7g o-fluorobenzoic acid (0.05mol) is dissolved in 20ml drying, slowly add CDI8.9g (0.055mol), after reacting 4h under room temperature, reaction solution is added drop-wise to by constant pressure funnel and is dissolved with piperazine dihydrochloride 20g (0.125mol), Piperazine anhydrous 10g (0.125mol), room temperature reaction suction filtration after 5 hours in the 60ml aqueous solution of sodium-chlor 14g, filtrate evaporate to dryness removing THF, 10ml extraction into ethyl acetate one time, NaOH saturated solution adjusts pH to 10, organic phase is merged after being extracted with ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for ethyl acetate, the white crystal of gained is 1-(2-fluoro benzoyl) piperazine crude product 4.7g, productive rate 45%.
5) 4-(6-{ [4-(trifluoromethyl) phenyl] amino } pyrimidine-4-yl) phenylformic acid passes through condensation reaction with 1-(2-fluoro benzoyl) piperazine, and the compound obtained is target compound 6-(4-{ [4-(2-fluoro benzoyl) piperazine-1-base] carbonyl } phenyl)-N-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine.
Measure the anhydrous THF of 20ml in the round-bottomed flask of 100ml, add triethylamine 4ml, be placed in ice bath and stir 10min, question response system cools, and drips isobutyl chlorocarbonate 1.5ml (10mmol) and reacts 10min formation thick white shape colloid.Reactant 4-(6-{ [4-(trifluoromethyl) phenyl] amino } pyrimidine-4-yl) phenylformic acid 1.8g (5mmol) and triethylamine 2.5ml are dissolved in dry THF; slowly dripped into by constant pressure funnel; dropwise the bath of recession deicing; room temperature reaction 10 hours; add reactant 1-(2-fluoro benzoyl) piperazine 1.56g (7.5mmol), room temperature reaction 24 hours.Evaporate to dryness tetrahydrofuran (THF); 40ml diluted ethyl acetate; saturated sodium bicarbonate solution washes three times; saturated sodium-chloride washes one time; organic phase anhydrous sodium sulfate drying spends the night, suction filtration, evaporate to dryness ethyl acetate; pillar layer separation (P:E=1:5) obtains target compound 6-(4-{ [4-(2-fluoro benzoyl) piperazine-1-base] carbonyl } phenyl)-N-[4-(trifluoromethyl) phenyl] pyrimidine-4-amine white solid 0.4g, productive rate 15%.
Gained compound structure is as follows:
Physico-chemical property: m.p=325 ~ 326 DEG C; EI-MS (m/z): 549.0 [M]
+.
Hydrogen spectrum nuclear magnetic resonance data: 1H NMR (DMSO-d6,400MHz): δ 10.2 (s, 1H), 8.9 (s, 1H), 8.05-8.19 (m, 2H), 7.98 (d, J=8.0Hz, 2H), 7.71 (d, J=8.0Hz, 2H), 7.58-7.67 (m, 2H), 7.49-7.56 (m, 1H), 7.39-7.48 (m, 1H), 7.40 (s, 1H), 7.19-7.35 (m, 2H), 3.39-3.91 (m, 8H).
Embodiment 2
In the structural formula of this inhibitor, R
1for fluorine atom, be in ortho position, R is fluorine atom, is in ortho position, by following steps preparation (see Fig. 1):
1) 4,6-dichloro pyrimidines and adjacent fluoroaniline generation nucleophilic substitution reaction prepare the chloro-N-of 6-(2-fluorophenyl) pyrimidine-4-amine;
Be dissolved in 40ml Virahol by 4,6-dichloro pyrimidine 3.88g (26mmol) and adjacent fluoroaniline 2.2 (20mmol), under the condition stirred, slowly drip the 1.5ml vitriol oil, heating reflux reaction monitored reaction system after 6 hours.Be cooled to room temperature after having reacted, put into 4 DEG C of refrigerator overnight, suction filtration after precipitation white solid, filter cake is put dry in an oven, obtain the chloro-N-of 6-(2-fluorophenyl) pyrimidine-4-amine crude product 4.0g, productive rate 92%.
2) para-bromo toluene is prepared Carboxybenzeneboronic acid through grignard reaction, esterification, hydrolysis, oxidizing reaction;
The step 2 of preparation method and embodiment 1) identical.
3) the chloro-N-of 6-(2-fluorophenyl) pyrimidine-4-amine prepares 4-{6-[(2-fluorophenyl) is amino] pyrimidine-4-yl with to Carboxybenzeneboronic acid through Suzuki linked reaction } phenylformic acid;
By chloro-for 6-N-(2-fluorophenyl) pyrimidine-4-amine 2.2g (10mmol), be placed in 250ml round-bottomed flask to Carboxybenzeneboronic acid (4-Carboxybenzeneboronic acid) 2g (12mmol), cesium carbonate 10g (30mmol), four triphenyl phosphorus palladium 0.6g (0.5mmol); add acetonitrile, each 50ml of water; nitrogen protection, 90 degrees Celsius of isothermal reactions 36 hours.Suction filtration while hot, by filtrate evaporate to dryness acetonitrile, one time is extracted with ethyl acetate 20ml, aqueous phase 6mol/L hydrochloric acid adjusts pH to 5, separate out white solid, suction filtration, filter cake is placed in baking oven inner drying, namely 4-{6-[(2-fluorophenyl) is amino] pyrimidine-4-yl is obtained } phenylformic acid crude product 2.5g, productive rate 83%.
4) o-fluorobenzoic acid and piperazine prepare 1-(2-fluoro benzoyl) piperazine by condensation reaction;
100g concentrated hydrochloric acid (12mol/L) is placed in the round-bottomed flask of 250ml, under the condition of ice bath, slowly adds 40g Piperazine anhydrous.After adding, remove ice bath, room temperature reaction spends the night, suction filtration, and filter cake is placed in baking oven inner drying, and gained white solid is piperazine dihydrochloride.Take the tetrahydrofuran (THF) that 7g o-fluorobenzoic acid (0.05mol) is dissolved in 20ml drying, slowly add CDI8.9g (0.055mol), after reacting 4h under room temperature, filtrate is added drop-wise to by constant pressure funnel in the 60ml aqueous solution being dissolved with piperazine dihydrochloride 20g (0.125mol), Piperazine anhydrous 10g (0.125mol), sodium-chlor 14g, room temperature reaction 5 hours.Suction filtration after reacting completely; filtrate evaporate to dryness removing THF; 10ml extraction into ethyl acetate one time, adds NaOH saturated solution and adjusts pH to 10, extraction into ethyl acetate 3 times; merge organic phase; organic phase anhydrous sodium sulfate drying spends the night, and suction filtration is spin-dried for ethyl acetate; the white crystal of gained is 1-(2-fluoro benzoyl) piperazine crude product 4.7g, productive rate 45%.
5) 4-{6-[(2-fluorophenyl) amino] pyrimidine-4-yl } phenylformic acid passes through condensation reaction with 1-(2-fluoro benzoyl) piperazine, and the compound obtained is target compound 6-(4-{ [4-(2-fluorophenyl) piperazine-1-base] carbonyl } phenyl)-N-(2-fluorophenyl) pyrimidine-4-amine.
Measure the anhydrous THF of 20ml in the round-bottomed flask of 100ml, add triethylamine 4ml, be placed in ice bath and stir after 10min question response system temperature declines, drip isobutyl chlorocarbonate 1.5ml (10mmol), reaction 10min generates thick white shape colloid.By reactant 4-{6-[(2-fluorophenyl) amino] pyrimidine-4-yl } phenylformic acid 1.5g (5mmol) is dissolved in dry THF with triethylamine 2.5ml; slowly added by constant pressure funnel; after dropwising; remove ice bath; room temperature reaction 10 hours; TLC monitors the generation of active intermediate, then adds reactant 1-(2-fluoro benzoyl) piperazine 1.56g (7.5mmol), room temperature reaction 24 hours.React rear evaporate to dryness tetrahydrofuran (THF), 40ml diluted ethyl acetate, saturated sodium bicarbonate solution washes three times, saturated sodium-chloride washes one time, organic phase anhydrous sodium sulfate drying spends the night, suction filtration, evaporate to dryness ethyl acetate, pillar layer separation (P:E=1:5) obtains target compound 6-(4-{ [4-(2-fluorophenyl) piperazine-1-base] carbonyl } phenyl)-N-(2-fluorophenyl) pyrimidine-4-amine white solid 0.39g, productive rate 17%.
Gained compound structure is as follows:
Physico-chemical property: m.p=198 ~ 199 DEG C; EI-MS (m/z): 498.9 [M]
+.
Hydrogen spectrum nuclear magnetic resonance data: 1H NMR (DMSO-d6,400MHz): δ 9.475 (d, J=12Hz, 1H), 8.695 (d, J=12Hz, 1H), 8.11-8.02 (m, 2H), 7.66-7.53 (m, 6H), 7.36-7.25 (m, 3H), 7.24-7.12 (m, 2H), 3.84-3.43 (m, 8H).
Embodiment 3
In the structural formula of this compound, R
1for fluorine atom, be in ortho position, R is ethanoyl, position between being in, and aliphatic amide is piperazine, by following steps preparation (see Fig. 1):
1) 4,6-dichloro pyrimidines and 1-(3-aminophenyl) ethyl ketone generation nucleophilic substitution reaction prepare 1-{3-[(6-chloropyrimide-4-base) is amino] phenyl } ethyl ketone;
By 4,6-dichloro pyrimidine 3.88g (26mmol) and 1-(3-aminophenyl) ethyl ketone 2.7g (20mmol) is dissolved in 40ml Virahol, under the condition stirred, dropwise add the 1.5ml vitriol oil, heating reflux reaction monitored reaction system after 6 hours.Be cooled to room temperature after reacting completely, put into 4 DEG C of refrigerator overnight, suction filtration after precipitation white solid, filter cake is put dry in an oven, obtain 1-{3-[(6-chloropyrimide-4-base) is amino] phenyl ethyl ketone crude product 4.5g, productive rate 91%.
2) para-bromo toluene is prepared Carboxybenzeneboronic acid through grignard reaction, esterification, hydrolysis, oxidizing reaction;
The step 2 of preparation method and embodiment 1) identical.
3) 1-{3-[(6-chloropyrimide-4-base) amino] phenyl } ethyl ketone with through Suzuki linked reaction prepared by 4-{6-[(3-acetylphenyl) phenyl] pyrimidine-4-yl to Carboxybenzeneboronic acid phenylformic acid;
By 1-{3-[(6-chloropyrimide-4-base) is amino] phenyl } ethyl ketone 2.5g (10mmol); 4-Carboxybenzeneboronic acid 2g (12mmol), cesium carbonate 10g (30mmol), four triphenyl phosphorus palladium 0.6g (0.5mmol) are placed in 250ml round-bottomed flask; add acetonitrile, each 50ml of water; nitrogen protection, 90 degrees Celsius of isothermal reactions 36 hours.Suction filtration while hot; by filtrate evaporate to dryness acetonitrile; one time is extracted with ethyl acetate 20ml; aqueous phase 6mol/L hydrochloric acid adjusts pH to 5; separate out white solid, suction filtration, filter cake is placed in baking oven inner drying; namely 4-{6-[(3-acetylphenyl) phenyl] pyrimidine-4-yl is obtained } phenylformic acid crude product 2.8g, productive rate 85%.
4) o-fluorobenzoic acid and piperazine prepare 1-(2-fluoro benzoyl) piperazine by condensation reaction;
100g concentrated hydrochloric acid (12mol/L) is placed in the round-bottomed flask of 250ml, under the condition of ice bath, slowly adds 40g Piperazine anhydrous.After adding, remove ice bath, room temperature reaction spends the night, suction filtration, and filter cake is placed in baking oven inner drying, and gained white solid is piperazine dihydrochloride.
Take the tetrahydrofuran (THF) that 7g o-fluorobenzoic acid (0.05mol) is dissolved in 20ml drying, slowly add CDI8.9g (0.055mol), 4h is reacted under room temperature, the active amide reaction solution of generation is added drop-wise to by constant pressure funnel in the 60ml aqueous solution being dissolved with piperazine dihydrochloride 20g (0.125mol), Piperazine anhydrous 10g (0.125mol), sodium-chlor 14g, room temperature reaction 5 hours.The removing of suction filtration after reacting completely, filtrate evaporate to dryness THF, 10ml extraction into ethyl acetate one time, NaOH saturated solution merge organic phase after adjusting pH to 10, extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying spends the night, suction filtration, be spin-dried for ethyl acetate; the white crystal of gained is 1-(2-fluoro benzoyl) piperazine crude product 4.7g, productive rate 45%.
5) 4-{6-[(3-acetylphenyl) phenyl] pyrimidine-4-yl } phenylformic acid and 1-(2-fluoro benzoyl) piperazine are by condensation reaction, and the compound obtained is target compound 1-(3-{ [6-(4-{ [4-(2-fluoro benzoyl) piperazine-1-base] carbonyl } phenyl) pyrimidine-4-yl] is amino } phenyl) ethyl ketone.
Measure the anhydrous THF of 20ml in the round-bottomed flask of 100ml, add triethylamine 4ml, be placed in ice bath and stir after 10min question response system temperature declines, dripping isobutyl chlorocarbonate 1.5ml (10mmol) and react 10min, form thick white shape colloid.By reactant 4-{6-[(3-acetylphenyl) phenyl] pyrimidine-4-yl } phenylformic acid 1.6g (5mmol) and triethylamine 2.5ml be dissolved in dry THF; slowly added by constant pressure funnel; after dropwising; remove ice bath; room temperature reaction 10 hours, TLC monitors the generation of reactive intermediate.Add reactant 1-(2-fluoro benzoyl) piperazine 1.56g (7.5mmol) room temperature reaction 24 hours.
React rear evaporate to dryness tetrahydrofuran (THF), 40ml diluted ethyl acetate, saturated sodium bicarbonate solution washed three times; saturated sodium-chloride washes one time; organic phase anhydrous sodium sulfate drying spends the night, suction filtration, evaporate to dryness ethyl acetate; pillar layer separation (P:E=1:5) obtains target compound 1-(3-{ [6-(4-{ [4-(2-fluoro benzoyl) piperazine-1-base] carbonyl } phenyl) pyrimidine-4-yl] is amino } phenyl) ethyl ketone white solid 0.47g, productive rate 18%.
Gained compound structure is as follows:
Physico-chemical property: m.p=244 ~ 246 DEG C; EI-MS (m/z): 523.1 [M]
+.
Hydrogen spectrum nuclear magnetic resonance data: 1H NMR (DMSO-d6,400MHz): δ 9.98 (s, 1H), 8.79 (s, 1H), 8.28 (s, 1H), 8.17-8.02 (m, 3H), 7.69-7.58 (m, 3H), 7.57-7.49 (m, 2H), 7.48-7.41 (m, 1H), 7.40-7.25 (m, 3H), 3.85-3.37 (m, 8H), 2.62-2.58 (s, 3H).
Embodiment 4
In the structural formula of this inhibitor, R
1for trifluoromethyl, position between being in, R is methoxyl group, position between being in, by following steps preparation (see Fig. 1):
1) 4,6-dichloro pyrimidines and m-anisidine generation nucleophilic substitution reaction prepare the chloro-N-of 6-(3-methoxyphenyl) pyrimidine-4-amine;
4,6-dichloro pyrimidine 3.88g (26mmol) and m-anisidine 2.46g (20mmol) is dissolved in 40ml Virahol, under the condition stirred, dropwise adds the 1.5ml vitriol oil, heating reflux reaction 6 hours monitoring reaction systems.Be cooled to room temperature after reacting completely, put into 4 DEG C of refrigerator overnight, suction filtration after precipitation white solid, filter cake is put dry in an oven, obtain the chloro-N-of 6-(3-methoxyphenyl) pyrimidine-4-amine crude product 4.4g, productive rate 95%.
2) para-bromo toluene is prepared Carboxybenzeneboronic acid through grignard reaction, esterification, hydrolysis, oxidizing reaction;
The step 2 of preparation method and embodiment 1) identical.
3) the chloro-N-of 6-(3-methoxyphenyl) pyrimidine-4-amine prepares 4-{6-[(3-methoxyphenyl) is amino] pyrimidine-4-yl with to Carboxybenzeneboronic acid through Suzuki linked reaction } phenylformic acid;
Chloro-for 6-N-(3-methoxyphenyl) pyrimidine-4-amine 2.4g (10mmol), 4-Carboxybenzeneboronic acid 2g (12mmol), cesium carbonate 10g (30mmol), four triphenyl phosphorus palladium 0.6g (0.5mmol) are placed in 250ml round-bottomed flask; add acetonitrile, each 50ml of water; nitrogen protection, 90 DEG C of isothermal reactions 48 hours.Suction filtration while hot, filtrate evaporate to dryness acetonitrile, one time is extracted with ethyl acetate 20ml, aqueous phase 6mol/L hydrochloric acid adjusts pH to 5, separate out white solid, suction filtration, filter cake is placed in baking oven inner drying, namely 4-{6-[(3-methoxyphenyl) is amino] pyrimidine-4-yl is obtained } phenylformic acid crude product 2.7g, productive rate 84%.
4) m-trifluoromethylbenzoic acid and piperazine prepare 1-[3-(trifluoromethyl) benzoyl] piperazine by condensation reaction;
100g concentrated hydrochloric acid (12mol/L) is placed in the round-bottomed flask of 250ml, under the condition of ice bath, slowly adds 40g Piperazine anhydrous.After adding, remove ice bath, room temperature reaction spends the night, suction filtration, and filter cake is placed in baking oven inner drying, and gained white solid is piperazine dihydrochloride.Take the tetrahydrofuran (THF) that m-trifluoromethylbenzoic acid 9.5g (0.05mol) is dissolved in 20ml drying, after reacting 4h under slowly adding CDI8.9g (0.055mol) room temperature, reaction solution is added drop-wise to by constant pressure funnel in the 60ml aqueous solution being dissolved with piperazine dihydrochloride 20g (0.125mol), Piperazine anhydrous 10g (0.125mol), sodium-chlor 14g, room temperature reaction 5 hours.Suction filtration after reacting completely; filtrate evaporate to dryness removing THF; 10ml extraction into ethyl acetate one time; NaOH saturated solution adjusts pH to 10, and merge organic phase after extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying spends the night; suction filtration; be spin-dried for ethyl acetate, the white crystal of gained is 1-[3-(trifluoromethyl) benzoyl] crude product 6.5g, productive rate 50%.
5) 4-{6-[(3-methoxyphenyl) amino] pyrimidine-4-yl } phenylformic acid passes through condensation reaction with 1-[3-(trifluoromethyl) benzoyl] piperazine, and the compound obtained is target compound N-(3-methoxyphenyl)-6-[4-({ 4-[3-(trifluoromethyl) benzoyl] piperazine-1-base } carbonyl) phenyl] pyrimidine-4-amine.
Measure the anhydrous THF of 20ml in the round-bottomed flask of 100ml, add triethylamine 4ml, be placed in ice bath and stir after 10min question response system temperature declines, drip isobutyl chlorocarbonate 1.5ml (10mmol) and react 10min and generate thick white shape colloid.By reactant 4-{6-[(3-methoxyphenyl) amino] pyrimidine-4-yl } phenylformic acid 1.6g (5mmol) is dissolved in dry THF with triethylamine 2.5ml, slowly be added drop-wise in above-mentioned solution by constant pressure funnel, after dropwising, remove ice bath, room temperature reaction 10 hours, TLC monitors.Reaction adds reactant 1-[3-(trifluoromethyl) benzoyl] piperazine 1.9g (7.5mmol), room temperature reaction 24 hours after generating activity anhydride intermediate.React rear evaporate to dryness tetrahydrofuran (THF); 40ml diluted ethyl acetate; saturated sodium bicarbonate solution washes three times; saturated sodium-chloride washes one time; organic phase anhydrous sodium sulfate drying spends the night, suction filtration, evaporate to dryness ethyl acetate; pillar layer separation (P:E=1:5) obtains target compound N-(3-methoxyphenyl)-6-[4-({ 4-[3-(trifluoromethyl) benzoyl] piperazine-1-base } carbonyl) phenyl] pyrimidine-4-amine white solid 0.5g, productive rate 18%.
Gained compound structure is as follows:
Physico-chemical property: m.p=84 ~ 86 DEG C; EI-MS (m/z): 561.3 [M]
+.
Hydrogen spectrum nuclear magnetic resonance data:
1h NMR (400MHz, DMSO) δ 9.80 (s, 1H), 8.76 (s, 1H), 8.10 (d, J=6.9Hz, 2H), 7.87 – 7.74 (m, 3H), 7.61 – 7.56 (m, 2H), 7.44 (s, 1H), 7.33 – 7.20 (m, 4H), 6.64 (d, J=6.2Hz, 1H), 3.77 (s, 3H), 3.66 – 3.32 (m, 8H).
Embodiment 5
In the structural formula of this inhibitor, R
1for fluorine atom, be in 3 and 4, R is methoxyl group, is in contraposition, by following steps preparation (see Fig. 1):
1) 4,6-dichloro pyrimidines and P-nethoxyaniline generation nucleophilic substitution reaction prepare the chloro-N-of 6-(4-methoxyphenyl) pyrimidine-4-amine;
4,6-dichloro pyrimidine 3.88g (26mmol) and P-nethoxyaniline 2.46g (20mmol) is dissolved in 40ml Virahol, under the condition stirred, dropwise adds the 1.5ml vitriol oil, heating reflux reaction 6 hours monitoring reaction systems.Be cooled to room temperature after reacting completely, put into 4 DEG C of refrigerator overnight, suction filtration after precipitation white solid, filter cake is put dry in an oven, obtain the chloro-N-of 6-(4-methoxyphenyl) pyrimidine-4-amine crude product 4.3g, productive rate 93%.
2) para-bromo toluene is prepared Carboxybenzeneboronic acid through grignard reaction, esterification, hydrolysis, oxidizing reaction;
The step 2 of preparation method and embodiment 1) identical.
3) the chloro-N-of 6-(4-methoxyphenyl) pyrimidine-4-amine prepares 4-{6-[(4-methoxyphenyl) is amino] pyrimidine-4-yl with to Carboxybenzeneboronic acid through Suzuki linked reaction } phenylformic acid;
By chloro-for 6-N-(4-methoxyphenyl) pyrimidine-4-amine 2.4g (10mmol); 4-Carboxybenzeneboronic acid 2g (12mmol); cesium carbonate 10g (30mmol); four triphenyl phosphorus palladium 0.6g (0.5mmol); be placed in 250ml round-bottomed flask; add acetonitrile, each 50ml of water, nitrogen protection, 90 degrees Celsius of isothermal reactions 48 hours.Suction filtration while hot, by filtrate evaporate to dryness acetonitrile, one time is extracted with ethyl acetate 20ml, aqueous phase 6mol/L hydrochloric acid adjusts pH to 5, separate out white solid, suction filtration, filter cake is placed in baking oven inner drying, namely 4-{6-[(4-methoxyphenyl) is amino] pyrimidine-4-yl is obtained } phenylformic acid crude product 2.8g, productive rate 86%.
4) 3,4-difluoro-benzoic acids and piperazine prepare 1-(3,4-difluoro benzoyl) piperazine by condensation reaction;
100g concentrated hydrochloric acid (12mol/L) is placed in the round-bottomed flask of 250ml, under the condition of ice bath, slowly adds 40g Piperazine anhydrous.After adding, remove ice bath, room temperature reaction spends the night, suction filtration, and filter cake is placed in baking oven inner drying, and gained white solid is piperazine dihydrochloride.Take 3,4-difluoro-benzoic acid 7.9g (0.05mol) is dissolved in the tetrahydrofuran (THF) of 20ml drying, slowly add CDI8.9g (0.055mol), after reacting 4h under room temperature, reaction solution is added drop-wise to by constant pressure funnel in the 60ml aqueous solution being dissolved with piperazine dihydrochloride 20g (0.125mol), Piperazine anhydrous 10g (0.125mol), sodium-chlor 14g, room temperature reaction 5 hours.Suction filtration after reacting completely; filtrate evaporate to dryness removing THF; 10ml extraction into ethyl acetate one time, NaOH saturated solution adjusts pH to 10, merges organic phase after extraction into ethyl acetate 3 times; organic phase anhydrous sodium sulfate drying spends the night; suction filtration, is spin-dried for ethyl acetate, and the white crystal of gained is 1-(3; 4-difluoro benzoyl) piperazine crude product 5.4g, productive rate 48%.
5) 4-{6-[(4-methoxyphenyl) amino] pyrimidine-4-yl } phenylformic acid and 1-(3; 4-difluoro benzoyl) piperazine passes through condensation reaction; the compound obtained is target compound 6-(4-{ [4-(3,4-difluoro benzoyl) piperazine-1-base] carbonyl } phenyl)-N-(4-methoxyphenyl) pyrimidine-4-amine.
Measure the anhydrous THF of 20ml in the round-bottomed flask of 100ml, add triethylamine 4ml, be placed in ice bath and stir after 10min question response system temperature declines, dripping isobutyl chlorocarbonate 1.5ml (10mmol) and react 10min, generate thick white shape colloid.By reactant 4-{6-[(4-methoxyphenyl) amino] pyrimidine-4-yl } phenylformic acid 1.6g (5mmol) is dissolved in dry THF with triethylamine 2.5ml, slowly add in above-mentioned solution by constant pressure funnel, after dropwising, remove ice bath, room temperature reaction 10 hours, TLC monitors the generation of activity anhydride intermediate.Add reactant 1-(3,4-difluoro benzoyl) piperazine 1.7g (7.5mmol), room temperature reaction 24 hours.React rear evaporate to dryness tetrahydrofuran (THF); 40ml diluted ethyl acetate; saturated sodium bicarbonate solution washes three times; saturated sodium-chloride washes one time, and organic phase anhydrous sodium sulfate drying spends the night, suction filtration; evaporate to dryness ethyl acetate; pillar layer separation (P:E=1:5) obtains target compound 6-(4-{ [4-(3,4-difluoro benzoyl) piperazine-1-base] carbonyl } phenyl)-N-(4-methoxyphenyl) pyrimidine-4-amine white solid 0.3g, productive rate 13%.
Gained compound structure is as follows:
Physico-chemical property: Mp228-231 DEG C, EI-MS (m/z): 529.1 [M]
+.
Hydrogen spectrum nuclear magnetic resonance data: 1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.07 (d, J=7.2Hz, 2H), 7.57 (d, J=6.3Hz, 6H), 7.38-7.28 (m, 1H), 7.16 (s, 1H), 6.95 (d, J=8.6Hz, 2H), 3.76 (s, 3H), 3.74-3.38 (m, 8H).
Measure N provided by the invention below, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor are to the kinase whose inhibit activities of Bcr-Abl, and measuring method is specific as follows:
Kinases ABL1 and substrate A bltide is purchased from Signal-Chem company, and select the ADP-GlobTM Kinase Assays detection kit of Promega company to detect the Inhibiting enzyme activity of target compound, working method illustrates according to test kit carries out.
By ATP (1mM) buffer (2 ×) (Tris 80mM, MgCl
220mM, BSA 0.2mg/mL, DTT2mM) dilute buffer (2 ×) solution that 80 times are mixed with ATP (125 μMs); The mixing solutions ATP solution of 125 μMs and Abltide liquor capacity 1:1 being hybridly prepared into ATP (62.5 μMs)-Abltide (0.5 μ g/ μ l) is for subsequent use; ABL1 kinase solution buffer (1 ×) (Tris 40mM, MgCl
210mM, BSA 0.1mg/mL, DTT 1mM) dilute buffer (1 ×) solution for standby that 100 times are mixed with ABL1 (10ng/ μ l);
Target compound (N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor) and positive control drug (Imatinib) buffer (1 ×) are mixed with 1.5 × 10 respectively
-5mol/L, 1.5 × 10
-6mol/L, 1.5 × 10
-7mol/L, 1.5 × 10
-8mol/L, 1.5 × 10
-9mol/L, 1.5 × 10
-10the sample solution of mol/L concentration gradient, on 384 orifice plates, every hole adds the mixing solutions of 2 μ L ATP-Abltide successively, 1 μ L sample solution, 2 μ L enzyme solution; Blank well adds the mixing solutions of 3 μ L damping fluids and 2 μ LATP-Abltide; Control wells adds the mixing solutions of 2 μ L ATP-Abltide, 1 μ L damping fluid, and 2 μ L enzyme solution, finish, hatch 60min at 30 DEG C; Add ADP-Glo reagent 5 μ L, at 25 DEG C, hatch 40min; Add Kinase detection reagent, at 25 DEG C, hatch 30min.Adopt the chemoluminescence module of the multi-functional microplate reader of PerkinElmer to measure the luminous value in every hole, computerized compound is to the inhibiting rate of ABL1 and IC
50.
N, the structural formula of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor is as follows:
N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor are to the result of Bcr-Abl kinase inhibiting activity, as shown in table 1:
Table 1. inhibitor is to the kinase whose inhibit activities result of Bcr-Abl (IC
50)
Result display N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor have stronger inhibit activities to Bcr-Abl kinases, and part N, the activity of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor is suitable with positive drug imatinib.Bcr-Abl kinases plays a significant role at cell signalling with in transforming, and it is by phosphorylation and a series of stream substrates of activation, and impel the unlimited hyperplasia of the ripe granulocyte of CML, Bcr-Abl does not express in normal cell, is the ideal targets for the treatment of CML.The object of Bcr-Abl inhibitor by suppressing Bcr-Abl kinase activity can reach treatment CML.
Carry out N below, the anticellular activities screening of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor: adopt mtt assay inspection N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor are to the growth inhibitory activity of K562 cell.
N provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor have antitumor action, vitro inhibition proliferation activity effect is had to tumour cell, there is the proliferation activity effect of inhibition tumor cell in human leukemia cell's (K562 cell), may be used for leukemic treatment.
The human leukemia cell's (K562 cell) taken the logarithm vegetative period, is diluted to 10 with RPMI1640 substratum
4the cell solution of individual/mL, is parallelly inoculated in (2000/hole) in 96 well culture plates, and every hole inoculation volume is 200 μ L, 37 DEG C, 5%CO
212h is cultivated in incubator.
Every hole adds testing compound (N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor) the 20 μ L of different concns, makes the final concentration of compound in hole be: 1.5 × 10
-7mol/L, 1.5 × 10
-6mol/L, 1.5 × 10
-5mol/L, 1.5 × 10
-4mol/L, each concentration establishes 3 multiple holes, and negative control adds cell and do not add compound, if 6 multiple holes, nilotinib is positive control, continues to cultivate 48h;
Every hole adds MTT (5mg/mL) 10 μ L, make the final concentration 0.5mg/mL of MTT in hole, 37 DEG C of incubators hatch 4h, supernatant is abandoned in careful suction, every hole adds DMSO 150 μ L, vibration 15min, and enzyme-linked immunosorbent assay instrument measures the ultraviolet absorption value (OD value) at 490nm place, each hole, then calculate cell inhibitory rate, and obtain IC according to inhibiting rate
50value;
The calculation formula of cell inhibitory rate is:
Inhibiting rate %=(control wells mean OD value-medication group mean OD value)/control wells mean OD value × 100%
Detected result shows: N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor have In-vitro Inhibitory Effect in various degree to K562 cell.
N provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor the results are shown in Table 2 to inhibiting tumour cells.
Table 2. inhibitor is to the inhibit activities result (IC of K562 cell
50)
Inhibitor prepared by result display can the growth of inhibition tumor cell, and N provided by the invention is described, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor are good to the proliferation inhibiting effect of tumour cell, can be applicable to the preparation of antitumor drug.
N provided by the invention, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, be the novel compound with Bcr-Abl kinase inhibiting activity, it is external has good inhibit activities to Bcr-Abl kinases, in view of the generation of Bcr-Abl kinases and chronic myelocytic leukemia develops closely related.Bcr-Abl inhibitor is by suppressing Bcr-Abl kinase whose activity can the propagation of anticancer effectively, and inducing cancer cell differentiation and apoptosis, can reach the object for the treatment of tumour; Experimental result shows prepared N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor can the growth of inhibition tumor cell, and partial inhibitor is suitable with positive drug to Bcr-Abl kinase inhibiting activity, N prepared by explanation, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor can be used for the preparation of antitumor drug.
Claims (10)
1. a N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, is characterized in that having following structural formula:
Wherein, R is monosubstituted base or disubstituted, and substituting group is alkyl or halogen; R
1for monosubstituted base or disubstituted, substituting group is alkyl or halogen.
2. N as claimed in claim 1,6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, is characterized in that, when described R is monosubstituted base, substituting group is positioned at the ortho position of amido on phenyl ring, a position or contraposition; R
1during for monosubstituted base, substituting group is positioned at the ortho position of carboxyl on phenyl ring, a position or contraposition;
Described R, R
1for time disubstituted, substituting group is identical or different, and the position of substitution is adjacent or alternate.
3. the N described in claim 1 or 2, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, is characterized in that, comprise following operation:
1) 4,6-dichloro pyrimidines prepare 6-chloro-N-substituted-phenyl pyrimidine-4-amine with containing substituent aniline generation nucleophilic substitution reaction;
2) 6-chloro-N-substituted-phenyl pyrimidine-4-amine with through Suzuki linked reaction prepared by 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid to Carboxybenzeneboronic acid;
3) react containing substituent phenylformic acid and piperazine the piperazine preparing monoamide;
4) piperazine of 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid and monoamide is by condensation reaction, obtains N, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
4. N according to claim 3, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, is characterized in that, described step 1) concrete operations be: by 4,6-dichloro pyrimidine be dissolved in Virahol containing substituent aniline, under the condition stirred, drip the vitriol oil, heating reflux reaction, after having reacted, be cooled to room temperature, be placed on 4 DEG C of refrigerator overnight, then suction filtration, dry cake, obtains 6-chloro-N-substituted-phenyl pyrimidine-4-amine crude product;
Described step 2) concrete operations be: by chloro-for 6-N-substituted-phenyl pyrimidine-4-amine crude product be dissolved in the mixed solvent of acetonitrile and water to Carboxybenzeneboronic acid; add cesium carbonate, tetrakis triphenylphosphine palladium; with nitrogen protection; isothermal reaction 24 ~ 48 hours at 90 DEG C; react after heat suction filtration; by filtrate evaporate to dryness removing acetonitrile; be extracted with ethyl acetate again, to be adjusted to pH be slightly acidic to aqueous phase concentrated hydrochloric acid; separate out solid; then suction filtration, dry cake, obtains 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid.
5. N according to claim 3, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, it is characterized in that, described step 3) concrete operations be: under condition of ice bath, added by piperazine in concentrated hydrochloric acid, then at room temperature stirring reaction spends the night, then suction filtration, dry cake, obtains piperazine dihydrochloride; To dissolve containing substituent phenylformic acid anhydrous tetrahydro furan, add CDI, room temperature reaction 2 hours, then dropwise joins in the saturated nacl aqueous solution of piperazine dihydrochloride and piperazine by it, room temperature reaction 6 hours, react rear evaporate to dryness tetrahydrofuran (THF), be extracted with ethyl acetate, aqueous phase sodium hydroxide solution is adjusted to pH=10, then is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, the then suction filtration of extraction, evaporate to dryness ethyl acetate, obtain the piperazine of monoamide.
6. N according to claim 3, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, it is characterized in that, described step 4) concrete operations be: under condition of ice bath, isobutyl chlorocarbonate is added drop-wise in the tetrahydrofuran (THF) containing triethylamine, be stirred to and produce thick white shape colloid, then the tetrahydrofuran solution of 4-(6-substituted aniline pyrimidine-4-yl) phenylformic acid and triethylamine is dripped wherein, dropwise the bath of recession deicing, at room temperature reaction is spent the night, generate activity anhydride, then the piperazine of monoamide is dripped wherein, at room temperature react 24 hours, reaction terminates rear evaporate to dryness tetrahydrofuran (THF), wash with saturated sodium bicarbonate successively, extraction into ethyl acetate, the organic phase anhydrous sodium sulfate drying of extraction, last suction filtration, evaporate to dryness ethyl acetate, obtain crude product, N is obtained again through pillar layer separation, 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
7. N according to claim 3, the preparation method of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor, it is characterized in that, the described preparation process to Carboxybenzeneboronic acid is: para-bromo toluene prepares grignard reagent p-tolylmagnesium bromide by grignard reaction, grignard reagent and trimethyl borate are obtained by reacting methylphenylboronic acid methyl esters, obtain methylphenylboronic acid to the hydrolysis of methylphenylboronic acid methyl esters, methylphenylboronic acid oxidation is obtained Carboxybenzeneboronic acid.
8. the N described in claim 1 or 2, the application of 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor in preparation Bcr-Abl inhibitor medicaments.
9. the N described in claim 1 or 2, the application in antitumor drug prepared by 6 diphenylpyrimidin-4-amine Bcr-Abl inhibitor.
10. apply as claimed in claim 9, it is characterized in that: described antitumor drug is the leukemic medicine for the treatment of.
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| CN105237496A (en) * | 2015-10-27 | 2016-01-13 | 济南大学 | New method for synthesizing N-tertbutyloxycarbonyl piperazine |
| CN106117254A (en) * | 2016-06-20 | 2016-11-16 | 许昌豪丰化学科技有限公司 | A kind of synthesis technique of Carboxybenzeneboronic acid |
| CN106565761A (en) * | 2016-11-15 | 2017-04-19 | 贵州大学 | Preparing technology for 4-carboxyphenylboronic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105237496A (en) * | 2015-10-27 | 2016-01-13 | 济南大学 | New method for synthesizing N-tertbutyloxycarbonyl piperazine |
| CN106117254A (en) * | 2016-06-20 | 2016-11-16 | 许昌豪丰化学科技有限公司 | A kind of synthesis technique of Carboxybenzeneboronic acid |
| CN106565761A (en) * | 2016-11-15 | 2017-04-19 | 贵州大学 | Preparing technology for 4-carboxyphenylboronic acid |
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